The two Alpine orogenic phases of the Eastern Alps, in the Cretaceous and in the Tertiary, were both accompanied by the formation of mineral deposits. However, subduction-related magmatic belts as well as the typical “Andean” ore deposits are missing. Therefore, the role of metamorphism in East Alpine metallogeny was tentatively explored for more than 60 y, although for a long time without tangible results. Microthermometric, geochemical and isotopic investigations of fluid inclusions from selected Alpine mineral deposits presented allow a preliminary confirmation of the involvement of metamorphic fluids in their origin. Deposits which were formed immediately after the first, Cretaceous orogeny, were produced at high pressures by fluids of very high salinity and high density, and with an isotopic composition of the water falling into the metamorphic field. These fluids are best understood as products of metamorphic de-volatilization of rocks of the subducted South Pennine domain. In contrast to this, the deposits formed after the second, Tertiary orogeny, originated at relatively low pressures from fluids with an appreciable content of CO2 and of low to moderate salinities. Isotopic compositions of this carbon indicate a deep crustal or even mantle source for CO2, while the water is isotopically more heterogeneous and may have mixed sources, both surficial and metamorphic. Tectonic control of these mineralizations is late-orogenic trans-tensional faulting, which exposed hot metamorphic rocks to fluid convection along brittle structures. These deposits conform best to the model of metamorphogenic metallogenesis by retrograde leaching, although ponded metamorphic fluids and mantle volatiles may also have been involved.